Series of nitrofuran compounds comprising 5-nitro-2-furyl 2-dialkyl-aminoalkyl ketone semicarbazone salts



Patented Dec. 22, 1953 UNITED STATES pPATENT OFFICE SERIES OF NITROFURAN COMPOUNDS M BRIS-ING .NITRO-Z-F'URYL fl-DIALKYL- AMINOALKYL KETONE SEMIGARBAZONE Kenyon J. Hayes, Norwich, Y.,.assignor to Eaton Laboratories, Inc., notation of New York Norwich, N. Y a cor- No Drawing. Application MayZB, 1950,

Serial No. 165.096

5 claims. 01. Mil-+2933) This series includes a number of closely related new compositions of matter which are referred to by the generic name 5-nitro-2-furyl2-dialkylaminoalkyl ketone semicarbazone salts. They are represented by the general structural formula:

in which:

R =hydrogen or a lower alkyl group.

R =hydrogen or a lower alkyl group.

R =a group containing as ,a soluble acid salt a tertiary nitrogen atom in a cyclized ring or having linked thereto 2 lower alkyl groups.

X :0 or S.

R hydrogen, a lower alkyl, lower hydroxyl alkyl or lower amino alkyl group when X=O, and when X=S R ==hydrogen or a lower alkyl group.

These substances may be conveniently prepared in a two-step process by conventional reactions. A 5-nitro-2-fury1 alkyl ketone, bearing two or more hydrogen atoms on the carbon atom alpha to the carbonyl group, may be causedto undergo a Mannich reaction with a simple aliphatic aldehyde and a secondary amine salt by proper choice of reaction conditions. The resulting S-nitro- 2 furyl 2-dialkylaminoalky1 ketone salt may then be condensed with the desired semicarbazide or thiosemicarbazide in slightly acid media to yield a compound of the type embraced within the above formula.

In order thatthe invention may be entirely available to those skilled in the art, methods for making some of the new compounds are described briefly:

5-nitro-2-furyl 3(1'-pi'peridino) ethyl lcctone semicarbazcme hydrochloride A mixture of 3.1 gms'. of pure 5-nitrc-2-furyl methyl ketone and. 2.68 gins. of piperidine hydrochloride and 1.0. gI Lfof paraformaldehyde in 15 cc. of n propanolcontaining 3 drops. of concentrated hydrochloric acid was refluxed one hour,-

a further quantity (0.5 gm.) of paraformaldehyde was added and refluxing continuedfor a total of five hours. The suspension was cooled, 50 cc. of ether added and the precipitated solid was filtered. l

The crude product was crystallized from an ethanol-Water mixturerfiflzw, 10sec. per gram) to yield 2.36 gm. of pure 5-nitro- 2-furyl fi-(lpiperidino) ethyl ketone hydrochloride. Melting point 206-8" C. with decomposition. Yield 41%. .Analyzed for chlorine: calculated, 12.3% C1; found, 12.6% Cl.

The semicarbazone of this ketone is readily prepared by partial evaporation of a solution of equimolar amounts of .(A) 5.-nitro-2-furyl fi-(lpiperidino) ethyl ketone hydrochloride and (B) semicarbazide hydrochloride. 10 parts of A, 3.86 parts'of B in 385 parts of water. Yellow needles,

highlylsoluble in water, P. 220-222- C. with decomposition.

EXAMPLE 2 fimttm-Z-juryl 'p-(l-m'pei'idino) ethyl ketcne 4- eshydrqzcycthyl semic rbczone hydrochloride QHzCHZ oaNfLo |Cl1-OHiCHwN CH2-HCI on on 2 NNHC ONHOHaCHrOH A mixture of 2.90 grams of 5-nitro-r2-fury1 /8-(1 piperidino) ethyl ketone, as prepared in Exampic .1. and 115.6 .grams of 4-(2-hydro1w1eethy1) .semicarbez de hydrochloride [prepared by heat- The solution is then evaporated to dryness at room temperature andthe crude yellow solid recrystallized from %ethanol; Yield 3.54 grams (88%) of melting point 2075-208 0. with decomposition.

EXAMPLE 3 5-nitro-2-furyl p-dimethylaminoethyl ketone semicarbazone hydrochloride NNHCONH:

by evaporation at room temperature to one-third volume. The white solid is filtered and washed with absolute ethanol. Recovery is 1.82 grams of white crystals of melting point 201-202" (3., with decomposition. Analysis: calculated for C9H13N2O4Cl; 43.4% C, 5.26% Hz: found; 43.5% C, 5.42% H.

Two hundred milligrams of the Mannich ketone, prepared above, is dissolved in 3 cc. of water and is treated at room temperature with a small excess of semicarbazide hydrochloride. The solution slowly becomes yellow and is evaporated to dryness at room temperature. The yellow crystals obtained are triturated with 1 cc. of water, filtered and washed with 3 cc. of absolute ethanol. The yield is 210 mgm. of yellow crystals of melting point 214-215 C., with decomposition. Analysis: calculated for C10H16N5O4C1; 22.9% N: found; 23.18% N.

EXAMPLE 4 ON 0 (6-0 H2GH2N NNHCIJNH:

One hundredth of a mole (2.89 grams) of 5-nitro- 2-furyl fi-(l-piperidino) ethyl ketone hydrochloride, as prepared for Example 1, and a molar equivalent (0.91 grams) of thiosemicarbazide are heated to 60 C. in '70 cc. of 70% ethanol containing 1 cc. of 4.5 N hydrochloric acid. The yellow solution is then evaporated to dryness at room temperature. The crude orange solid is purified by recrystallization from 50 cc. of 70% ethanol, using charcoal. The yield is 1.70 grams of melting point 193-194 C., with decomposition. Analysis: calculated for C13H20N5O3SC1; 19.35% N: found; 19.29% N.

What I claim is:

1. A compound having chemotherapeutic activity and high water solubility, and represented by the formulae:

and

r r ON 0 co-( JR= u H H 1101 NEG-NEE.

inwhich:

R represents a member of the group consisting of hydrogen and lower alkyl R2 represents a member of the grou consisting of hydrogen and lower alkyl R3 represents a member of the group consisting of di-lower alkylamino and piperidyl radicals R4 represents a member of the group consisting of hydrogen, lower alkyl, lower hydroxy alkyl and lower amino alkyl R5 represents a member of the group consisting of hydrogen and lower alryl.

2. S-nitro-Z-furyl fi-(l-piperidino) ethyl ketone semicarbazone hydrochloride.

3. E-nitro-Z-furyl e-(l-piperidino) ethyl ketone 4-,3-hydroxyethyl semicarbazone hydrochloride represented by the formula:

CHECfi:

NNHC ON'HCHiCHiOH 4. 5-nitro-2-furyl ,B-dimethylaminoethyl ketone semicarbazone hydrochloride represented by the NNHC ONE:

5. 5-nitro-2-furyl B-(l-piperidino) ethyl ketone thiosemicarbazone hydrochloride represented by the formula:

NNHC NH: C HzCH:

KENYON J. HAYES.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,416,235 Steelman et a1 Feb. 18, 1947 2,416,237 Steelman et al. Feb. 18, 194'? 2,416,239 Steelrnan et al Feb. 18, 1947 OTHER REFERENCES Paul et al.: Jour. Pharm. and Exp. Therapeu., (February 1950, pp. 153-7) Dreizen: J. of Dental Research, vol. 28, No. 3,

" June 1949, pp. 288-298. 

1. A COMPOUND HAVING CHEMOTHERAPEUTIC ACTIVITY AND HIGH WATER SOLUBILITY, AND REPRESENTED BY THE FORMULAE: 